Skip to main content
Download PDF

Patient-centered assessment of treatment for alpha-1 antitrypsin deficiency: literature review to identify concepts and measures for people with alpha1-antitrypsin deficiency

Orphanet Journal of Rare Diseases volume 20, Article number: 83 (2025) Cite this article

Abstract

Background

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that can result in a range of illnesses, with chronic obstructive pulmonary disease (COPD) being one of the most common. Although some people obtain genetic testing that identifies AATD, many people are unaware that they have AATD until they develop COPD, often at a younger age than is typical. Treatment for AATD consists primarily of augmentation with AAT, requiring weekly infusions of blood products for most patients. This treatment can slow disease progression and improve symptoms, but is burdensome; thus, people with AATD could benefit from additional or alternate treatments. However, to guide the development of new treatments, researchers need to identify which outcomes matter to people with AATD.

Methods

We conducted a scoping literature review to better understand patient experiences with AATD and its treatment and identify patient-reported outcome measures (PROMs) used to assess symptoms and impacts in studies of people with AATD.

Results

The review identified 44 concepts related to symptoms and disease burden, grouped into six domains (symptoms, physical function, cognitive function, emotional function, psychosocial function, and treatment burden) and 24 PROMs that have been used in research on AATD. None of the identified measures were developed specifically for people with AATD. Research on patient-focused outcomes was limited, suggesting a significant gap in knowledge.

Conclusions

People with AATD experience a variety of disease-related burdens, but this study showed there is a lack of published, in-depth studies to support selection and evaluation of patient-centered outcomes among populations of people with AATD. A limited number of PROMs have been used in research on AATD or in clinical trials of treatment, including COPD-specific measures that assess symptoms and quality of life and measures of mood, sleep, and general physical and psychosocial functioning. The current study documented the available evidence and compiled a list of potential concepts of interest, but further qualitative and quantitative studies will be needed to understand the outcomes that matter to people with AATD and to evaluate the alignment between these outcomes and available measures.

Background

Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder caused by mutations of the SERPINA1 gene. These mutations result in low serum levels of AAT, which is a protease inhibitor that protects tissue from damage by neutrophil proteases [1, 2]. AATD is associated with increased risk of developing lung disease and some genetic variants are associated with more severe disease and higher risk of mortality [3]. AATD also imposes a significant disease and economic burden on patients [4]. People with AATD have a higher risk of lung disease development at a younger age than is typical, especially when compounded by other factors, such as smoking or exposure to airborne pollutants [3]. Although the precise prevalence is challenging to determine, some studies suggest that AATD may be significantly underdiagnosed, or diagnosis may be delayed, due to limited genetic screening practices and inconsistent testing of people with illnesses associated with AATD [1, 5]. Early detection of AATD is vital because therapy to augment AAT and behavioral modifications (e.g., smoking cessation) may provide protection against disease [6].

To date, clinical research on AATD with or without lung disease has focused on epidemiological studies to determine the prevalence of different genotypes, assess specific morbidity and mortality outcomes, and clinical trials of augmentation therapy intended to understand specific aspects of treatment, such as the optimal dosing to prevent lung function deterioration [4, 7]. Although these studies help describe the incidence of AATD within various populations around the world and increase knowledge of AATD as a contributor to lung disease, they provide limited insight into the specific outcomes that matter to patients when considering treatment options. Recent published trials of treatment for AATD have typically included clinical assessments of AAT serum levels and lung function [8,9,10,11], with only a few including patient-reported outcome measures (PROMs) such as general assessments of health-related quality of life (HRQOL) or measures of the symptoms and impacts of chronic obstructive pulmonary disease (COPD) [12]. PROMs have been used more often in observational studies that seek to correlate AATD and its varied genotypes to different levels of patient burden from disease, including increased burden that may result from delayed diagnosis or early onset of lung symptoms [13,14,15].

To better understand patient experiences with AATD and its treatment, this scoping review [16] study aimed to assess two types of published literature on AATD: qualitative research studies or other resources containing testimony from people who have AATD (with or without a diagnosis of lung disease) and observational or clinical research studies of people with AATD that included the use of a PROM. The review aimed to extract data about the health-related concepts that may be relevant to patients when considering treatment options and to identify the PROMs that have been used to evaluate health-related quality of life and functioning outcomes for the AATD population.

Methods

A broad scoping strategy for retrieving potentially useful publications was developed because AATD is an uncommon health condition and research on patient-centered outcomes appeared to be limited (Fig. 1. Overview of Study Steps. Searches were conducted in Embase and PubMed, two comprehensive bibliographic databases of health science literature, on February 9, 2023 and March 13, 2023 respectively, for all publications referencing AATD and lung symptoms or diseases (search strategy provided in Additional file 1, Table 1). All retrieved records were downloaded and combined into a single bibliographic database using EndNote 20 software. This procedure resulted in a study-specific EndNote database of English language publications dating from 2010 or later that were indexed by Embase or PubMed and included at least one term for AATD and one term for lung function, disease, or impairment. This EndNote database was then used to execute a series of searches to identify publications on specific topics of interest (search strategies are provided in Additional file 1, Table 2). These searches were intended to retrieve articles that addressed one or more of the following: qualitative research studies with an AATD population and studies of any type that addressed HRQOL, such as patient experiences, quality of life, functioning or disability, or symptom burden, in people with AATD. Bibliographic records that were responsive to these search strategies were grouped and reviewed for adherence to several inclusion and exclusion criteria, shown in Table 1. Finally, to identify articles about PROMs that have been used in AATD populations, the EndNote database was searched for the names and acronyms of PROMs as they were identified during the reviews of titles and abstracts and during full-text review.

Fig. 1
figure 1

Overview of study steps

Full size image
Table 1 Inclusion and exclusion criteria for qualitative and HRQOL studies
Full size table

Despite the size of the EndNote database, the topical searches produced limited useful results. Consequently, a series of additional searches and supplementary strategies were used to identify additional publications relevant to understand people’s experiences with AATD. These ad hoc searches included searches for new terms identified during article review (e.g., the names of specific symptoms or PROMs); ‘snowball’ searches for articles identified in references lists; searches using Google and Bing search engines; use of the ‘similar article’ function in PubMed; and using Google Scholar and Web of Science to retrieve and review lists of articles that cited publications that had been identified as highly relevant during article review. All primary and ad hoc searches were conducted by a trained and experienced research librarian and items retrieved by added searches were added to the EndNote database. Finally, to further improve the scope of the review due to the limited retrieval of useful publications, the inclusion criteria were adjusted to permit the inclusion of two key source documents that do not qualify as research studies: the US Food and Drug Administration’s (FDA) Voice of the Patient report [17], which reports on a public meeting held in September, 2015, to hear from patients with AATD, and the Big Fat Reference Guide [18], a patient-centered resource guide developed by AlphaNet, the advocacy affiliate of the Alpha-1 Foundation.

Two analysts independently reviewed all publications to determine whether they reported information about AATD-related patient experiences, including experiences of symptoms or impacts of lung impairment/disease among people with AATD or the use of PROMs to assess symptoms and impacts in an AATD patient population. The two analysts then extracted data from relevant publications. Extracted variables included aspects of the source material (e.g., study type), terms or phrases used to describe symptoms or impacts of AATD or AATD-related lung disease, and information about any PROMs used to assess symptoms or impacts.

To develop a broad conceptual understanding of patient experiences with AATD, specific terms and phrases used in publications to describe symptoms and impacts of AATD or AATD-related lung disease were classified to group similar items together with a unified concept label. For example, the terms ‘improved sleep,’ ‘sleep disturbance,’ and ‘sleep quality’ were grouped together under the overarching concept label ‘sleep.’ The overarching concepts were subsequently grouped together into domains based on their similarity and interrelationships. For example, concepts like ‘cough’ and ‘dizziness’ were placed together in the Symptom domain, while concepts like ‘sleep’ and ‘basic mobility’ were grouped under the Physical Function domain.

To develop a more detailed understanding of the PROMs that have been used with the AATD population in research studies, details about measures (e.g., number of items, recall period, scoring) were extracted from publications when available. Gaps in information were addressed by reviewing original publications describing the instrument or available information provided by measure management organizations (e.g., Mapi Research Trust). For each measure identified, a supplementary search of ClinicalTrials.gov, a central repository of clinical trial protocol records, was conducted to determine whether the PROM had been used in any clinical trials of treatment for AATD that began 2010 to March 2023; trials that had been suspended or withdrawn were excluded.

Results

The baseline searches retrieved 2572 non-duplicative publication records from Embase and PubMed that were added to EndNote. EndNote’s automated algorithms identified one publication that had been retracted and 21 publications that were duplicates, resulting in 2550 publications. Seven additional publications relevant to the aim of understanding AATD patient experiences were identified through ad hoc searches, resulting in a total of 2557 publications in the EndNote database. Search results described below were obtained by conducting subsequent searches within this EndNote database. As shown in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram (Fig. 2), searches for qualitative studies and studies reporting on symptom burden, patient experiences, quality of life, and disability or functioning, plus publications retrieved by added searches, produced a total of 238 publications from the EndNote database. On review of titles and abstracts, 206 publications were excluded and 32 were included in the full text review. Two publications were excluded during full text review, resulting in a set of 30 publications included in data extraction [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. These 30 publications included reviews (n = 7), observational studies (n = 14), longitudinal studies (n = 3), qualitative studies (n = 4), and report/guides containing patient testimony (n = 2).

Fig. 2
figure 2

PRISMA diagram for qualitative and HRQOL review. *Sums to more than 238 because some items were retrieved by more than one search strategy

Full size image

Concepts in AATD patient experience

A total of 112 descriptive terms for patient-centered health experiences related to symptoms and disease burdens were found across the publications reviewed (Additional file, Table 3). Conceptually similar or highly related terms were grouped together. For example, Wienke et al. refer both to behavior modification related to susceptibility to disease and to avoidance behaviors regarding environmental exposure [31], which were grouped together with other similar terms under the concept label ‘behavior burden and vigilance.’ After grouping similar terms together, a total of 44 uniform concepts were identified and grouped into 6 domains, including four domains for functioning, one for symptoms, and one for treatment burden (Table 2).

Table 2 Domains and concepts identified from the literature
Full size table

The concepts and domains in Table 2 encompass the experiences of both individuals with AATD and lung disease and those who know they have AATD but do not yet have any lung disease symptoms. The findings suggest that people who know they have AATD but are asymptomatic (generally healthy) may experience emotional impacts (e.g., anxiety, depression) and burdens from living with uncertainty, which may include changes in lifestyle, behavior, and occupation to minimize environmental exposures. People with AATD who have developed lung symptoms experience additional burdens due to the specific symptoms, exacerbations, and impacts of disease, as well as the burden of augmentation therapy to treat AATD.

The symptoms domain includes symptoms of lung disease, some of which may be experienced differently or at an earlier age by individuals with AATD. Sandhaus et al. [36] observed that while exacerbation frequency is similar among people with AATD and COPD and people with COPD who do not have AATD, people with AATD may experience more severe exacerbations, and progression of lung disease in people with AATD is strongly affected by exacerbation frequency. Accordingly, the treatment burdens domain encompasses both burdens of augmentation therapy for AATD and treatments for lung disease.

The cognitive function domain includes the ability to concentrate, memory, and slurred speech, which are symptoms that can occur during acute pulmonary exacerbations in people with AATD and lung disease [18]. The emotional function domain includes multiple concepts that are relevant to both people with lung disease and those who have AATD but are still generally healthy. Anger, anxiety, depression, fear, and loss of control can result from the uncertainty of living with the knowledge that one has AATD and worries about the future impacts of AATD-related illness on oneself and one’s family [41]. Anger, depression, anxiety, stress, and fear are also related to the burden of dealing with lung disease symptoms and impacts on functioning [18, 41]. Irritability and mood changes are mentioned in the AlphaNet guide [18] specifically as potential signs of an acute exacerbation.

The physical function domain includes the impact of lung disease on basic daily activities, activities that require physical exertion and mobility. This domain also includes exercise and nutrition considerations for both those with and without lung disease. Exercise and nutrition are mentioned in the AlphaNet guide [18] for healthy people with AATD as they can help in limiting other health problems that could further exacerbate future lung disease. Difficulty exercising and maintaining adequate nutrition are also mentioned in the AlphaNet guide as limitations for those living with lung disease. Finally, the sleep concept includes general sleep disturbance and sleep apnea, which can be magnified by lung disease.

Many of the concepts in the psychosocial function domain encompass experiences of people with lung disease and healthy people with AATD. Lifestyle adaptations, such as changing jobs or avoiding environmental exposures, required to minimize disease risk or manage lung disease create a burden for people with AATD and can impact their social and family life [19, 20, 47]. Reproductive health or family planning is also a concern for people with AATD due to the fear of passing the gene on to one’s children [17, 31]. Sexual function can be affected by symptoms of lung disease and is discussed in the AlphaNet guide section on managing lung disease [18].

Patient reported outcome measures identified

The review identified 24 PROMs that have been used in studies of people with AATD and lung disease (Table 3). However, none of the identified measures were developed specifically for people with AATD and the majority have been used infrequently in this population (i.e., 14 measures were referenced in only 1–2 publications). Two PROMs, the St. George’s Respiratory Questionnaire (SGRQ) and the EQ-5D-5L, have also been used in recent clinical trials of AATD treatment (see Table 4). The three most commonly used measures were the COPD Assessment Test (CAT), Modified Medical Research Council dyspnea scale, and the SGRQ. An FDA guidance document [48] specific to the SGRQ was identified during follow-up searches to retrieve information about the PROM’s content and recall period. This document notes that FDA has determined that the SGRQ and the alternate SGRQ-C version (a shorter version tailored specifically for COPD) are suitable for use as a coprimary or secondary endpoint for treatment efficacy assessment in a clinical trial for COPD. The document shares specific recommendations and limitations that pertain to the use of the SGRQ or SGRQ-C in the context of an FDA regulatory review, but does not specifically address suitability for trials within an AATD population. However, the SGRQ has been used for secondary or exploratory endpoints in five recent clinical trials of treatment for people with AATD and lung disease (Table 4).

Table 3 Measures identified in the review
Full size table
Table 4 Clinical trials of treatment for AATD that included a PROM
Full size table

Discussion

This scoping review identified 44 concepts that reflect symptoms and impacts of AATD and AATD-related lung disease, and provide a broad picture of life with this health condition. These concepts demonstrate that a diagnosis of AATD conveys burdens for patients, including the genetic diagnosis itself and treatment burden, and that AATD-related lung disease results in additional symptoms and impacts related to lung function. Our findings also indicate that some symptoms and impacts of lung disease may differ between people with and without AATD. These differences appear linked to the age of disease onset, disease severity and rate of progression.

These general findings highlight limitations of the literature, specifically the lack of published, in-depth qualitative studies examining the lived experiences of people with AATD. This poses a significant obstacle to understanding which outcomes are most meaningful to patients in relation to treatment benefit, a necessary precursor to selecting a PROM for use in a clinical trial. For example, qualitative study findings suggest that anxiety experiences associated with a genetic diagnosis are important, but it is unclear whether people with AATD regard these as relevant to the assessment of treatment outcomes. Similarly, AATD-related lung disease progression may be affected by exacerbation frequency, but it is unclear how exacerbations should be assessed or whether patients themselves are able to report them reliably. Choate et al. [27] reported that people with AATD and lung impairment recognized about half of the exacerbations they experienced, with low correlation between health care utilization based and symptoms-based definitions of exacerbation.

Although several PROMs have been used in studies of people with AATD and lung disease, these PROMs are not specific to AATD, and the review identified only two PROMs that had been used in clinical trials of AATD treatment (i.e., EQ5D-5L and SGRQ). Qualitative and psychometric studies of PROMs within the AATD population appear to be lacking, and are needed to understand the relevance of measure content and the meaningfulness of changes in score for this population. Finally, from the patient’s perspective, an ideal treatment pathway for AATD might include early identification of the genetic disorder followed by treatment that effectively prevents disease altogether, greatly extends the period of disease-free years, or greatly slows the progression of early lung symptoms and impacts. For such a treatment, currently available PROMs may not be applicable.

Limitations of the study

Because of the limited number of published qualitative studies of people with AATD, evidence from studies that used questionnaires to gather data as well as other types of resources, such as the AlphaNet patient guide, were used to identify potentially relevant outcome concepts. These sources of information do not provide ‘gold standard’ evidence for the outcomes that matter to patients because they are subject to various forms of limitation and bias. For example, questionnaire-based studies limit the outcomes that people can report to those selected by researchers and non-traditional resources may blend the perspectives of clinicians or other stakeholders with those of patients. Additional qualitative studies are needed to affirm or expand the understanding of the experiences of people with AATD, including explorations of how they experience COPD and what treatment outcomes are most important to them.

This study focused on reviewing literature related to experiences of AATD and AATD-related lung disease. Literature focused on the experiences of people with other AATD-related illnesses may have provided additional relevant insights on selected topics, such as treatment burden associated with AAT augmentation therapy, and may have resulted in the identification of additional measures.

Conclusions

People with AATD experience a variety of burdens associated with the genetic diagnosis itself and with lung impairments or disease that may develop due to AATD. However, the limited amount and scope of qualitative study publications focused on patient experiences of AATD and associated lung disease hampers understanding of how best to assess patient-centered outcomes of treatment among populations of people with AATD. No AATD disease-specific PROMs were identified. A limited number of PROMs have been used in research on AATD, including COPD-specific measures that assess symptoms and quality of life and measures of mood, sleep, and general physical and psychosocial functioning. Most of these PROMs have been used in only one or two studies. In clinical trials of AATD treatments, the use of PROMs was limited, with just two PROMs being used over more than a decade. As a result, there is little information to guide investigators who wish to select a PROM for use in understanding the experiences of people with AATD or for evaluating treatment benefits for this population.

To address these gaps, well-designed qualitative studies are needed to elicit comprehensive data about the lived experiences and treatment priorities of diverse samples of people with AATD, both with and without lung disease. Incorporating patients’ lived experience in drug development is a key goal of the Critical Path for Alpha-1 Antitrypsin Deficiency (CPA-1) Consortium and part of FDA patient focused drug development guidance [49, 50]. Such studies would provide crucial data needed to understand the outcomes that matter to people with AATD and to evaluate the alignment between these outcomes and the available PROMs. For any PROMs that appear to have suitable content, additional qualitative or psychometric studies may also be needed to evaluate their measurement properties. Finally, a better understanding of the experiences of people with AATD, assessed both qualitatively and quantitatively, could help identify concepts of interest that are relevant to different pathways for treatment or identify potential new pathways for treatment, including non-pharmacological therapies and improvements to healthcare or treatment delivery, such as making it easier for people to obtain augmentation therapy at home.

Availability of data and materials

All data extracted from the included studies are available via PubMed, Embase, Google Scholar, or websites as listed in the references section.

Abbreviations

AAT:

Alpha-1 antitrypsin

AATD:

Alpha-1 antitrypsin deficiency

CAT:

COPD assessment test

COPD:

Chronic obstructive pulmonary disease

FDA:

U.S. Good and Drug Administration

HRQOL:

Health related quality of life

PROM:

Patient reported outcome measure

SGRQ:

St. George’s Respiratory Questionnaire

SGRQ-C:

St. George’s Respiratory Questionnaire, COPD version

References

  1. Greulich T, Vogelmeier CF. Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis. Ther Adv Respir Dis. 2016;10(1):72–84.

    Article  CAS  PubMed  Google Scholar 

  2. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443–55.

    Article  CAS  PubMed  Google Scholar 

  3. Meischl T, Schmid-Scherzer K, Vafai-Tabrizi F, Wurzinger G, Traunmüller-Wurm E, Kutics K, et al. The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency: Results from the austrian alpha-1 lung registry. Respir Res. 2023;24(1):34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Miravitlles M, Herepath M, Priyendu A, Sharma S, Vilchez T, Vit O, et al. Disease burden associated with alpha-1 antitrypsin deficiency: Systematic and structured literature reviews. Eur Respir Rev. 2022;31(163):66.

    Article  Google Scholar 

  5. Ashenhurst JR, Nhan H, Shelton JF, Wu S, Tung JY, Elson SL, Stoller JK. Prevalence of alpha-1 antitrypsin deficiency, self-reported behavior change, and health care engagement among direct-to-consumer recipients of a personalized genetic risk report. Chest. 2022;161(2):373–81.

    Article  CAS  PubMed  Google Scholar 

  6. Greulich T. Alpha-1-antitrypsin deficiency: Disease management and learning from studies. COPD J Chronic Obstr Pulm Dis. 2017;14:S8–11.

    Article  Google Scholar 

  7. López-Campos JL, Hernandez LC, Eraso CC. Implications of a change of paradigm in alpha1 antitrypsin deficiency augmentation therapy: From biochemical to clinical efficacy. J Clin Med. 2020;9(8):1–19.

    Article  Google Scholar 

  8. Stoller JK. Designing clinical trials in “regular” copd versus alpha-1 antitrypsin deficiency-associated copd: “More alike than unalike?” Chronic Obstr Pulm Dis. 2022;9(1):95–102.

    PubMed  Google Scholar 

  9. Geraghty P, Campos MA. Cytokine regulation by alpha 1 antitrypsin therapy: a pathway analysis of a pilot clinical trial. Am J Respir Crit Care Med. 2022;205(1):697.

    Google Scholar 

  10. Campos M, Geraghty P, Holt G, Donna E, Mendes E, Escobar LA, et al. The biological effects of double dose augmentation therapy for subjects with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2017;195:6315.

    Google Scholar 

  11. Steinkamp G, Köhnlein T, Ley-Zaporozhan J, Wegscheider K, Buhl R. Clinical trial endpoints in alpha-1-antitrypsin deficiency: interdisciplinary aspects. Pneumologie. 2011;65(4):229–35.

    Article  CAS  PubMed  Google Scholar 

  12. Hogarth DK, Delage A, Zgoda MA, Reed MF. Evaluation of the safety and effectiveness of the spiration valve system for single lobe treatment of severe emphysema in patients with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2018;197(MeetingAbstracts):66.

    Google Scholar 

  13. Tejwani V, Nowacki AS, Fye E, Sanders C, Stoller JK. The impact of delayed diagnosis of alpha-1 antitrypsin deficiency: the association between diagnostic delay and worsened clinical status. Respir Care. 2019;64(8):915–22.

    Article  PubMed  Google Scholar 

  14. Manca S, Rodriguez E, Huerta A, Torres M, Lourdes L, Curi S, et al. Health-related quality of life in emphysema due to alpha-1-antitrypsin deficiency. Eur Respir J. 2013;42:66.

    Google Scholar 

  15. Schramm GR, Mostafavi B, Piitulainen E, Wollmer P, Tanash HA. Lung function and health status in individuals with severe alpha-1-antitrypsin deficiency at the age of 42. Int J COPD. 2021;16:3477–85.

    Article  Google Scholar 

  16. Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol. 2018;18(1):143.

    Article  PubMed  PubMed Central  Google Scholar 

  17. US Food and Drug Administration. The voice of the patient: Patient-focused drug development for alpha-1 antitrypsin deficiency; 2016.

  18. AlphaNet. Big fat reference guide [Requires free account registration]. https://bfrg.alphanet.org/.

  19. Anzueto A. Alpha-1 antitrypsin deficiency-associated chronic obstructive pulmonary disease: a family perspective. COPD J Chronic Obstr Pulmon Dis. 2015;12(4):462–7.

    Article  Google Scholar 

  20. Barjaktarevic I, Campos M. Management of lung disease in alpha-1 antitrypsin deficiency: What we do and what we do not know. Therap Adv Chronic Dis. 2021;12(suppl 1):66.

    Google Scholar 

  21. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy: systematic review. Danish Med Bull. 2010;57(9):66.

    Google Scholar 

  22. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2016;2016(9):66.

    Google Scholar 

  23. Holm KE, Borson S, Sandhaus RA, Ford DW, Strange C, Bowler RP, et al. Differences in adjustment between individuals with alpha-1 antitrypsin deficiency (aatd)-associated copd and non-aatd copd. COPD J Chronic Obstr Pulm Dis. 2013;10(2):226–34.

    Article  Google Scholar 

  24. Manca S, Rodriguez E, Huerta A, Torres M, Lazaro L, Curi S, et al. Usefulness of the cat, lcopd, eq-5d and copdss scales in understanding the impact of lung disease in patients with alpha-1 antitrypsin deficiency. COPD J Chronic Obstr Pulmon Dis. 2014;11(5):480–8.

    Article  Google Scholar 

  25. Tian X, Solomon DH, Smith RA. A stress buffering perspective on the progression of alpha-1 antitrypsin deficiency. Health Commun. 2020;35(6):747–55.

    Article  PubMed  Google Scholar 

  26. Torres Redondo M, Campoa E, Ruano L, Sucena M. Health-related quality of life in patients with alpha-1 antitrypsin deficiency: a cross sectional study. Arch Bronconeumol. 2017;53(2):49–54.

    Article  PubMed  Google Scholar 

  27. Choate R, Sandhaus R, Holm K, Mannino D, Strange C. Patient-reported pulmonary symptoms and exacerbations in a cohort of patients with alpha-1 antitrypsin deficiency. Chest. 2021;160(4):A1793–4.

    Article  Google Scholar 

  28. Choate R, Sandhaus RA, Holm K, Mannino DM, Strange C. Management of pulmonary exacerbations in a cohort of patients with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2022;205(1):66.

    Google Scholar 

  29. Stoller JK, Smith P, Yang P, Spray J. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey. Cleve Clin J Med. 1994;61(6):461–7.

    Article  CAS  PubMed  Google Scholar 

  30. Raveendran S, Burke M, Singh D, Karim A, Macrayan E, Patton A, et al. Alpha-1 insight: a mixed method, retrospective/prospective, descriptive study of diagnostic journey, experiences, and insights of patients with alpha-1-antitrypsin deficiency. J Allergy Clin Immunol. 2023;6:AB182.

    Article  Google Scholar 

  31. Wienke S, Strange C, Walker D, Sineath M, Quill J, Warner B, et al. Social impact identified in and by the alpha-1 antitrypsin deficiency community. Rare Dis Orphan Drugs. 2014;1(3):75–82.

    Google Scholar 

  32. Herepath M, Miravitlles M, Priyendu A, Greulich T, Sharma S, Vilchez T, et al. Pro60 clinical and economic burden associated with alpha-1 antitrypsin deficiency (aatd) in adults: Systematic and targeted literature reviews. Value Health. 2020;7:100.

    Google Scholar 

  33. Worthington AK, Parrott RL, Smith RA. Spirituality, illness unpredictability, and math anxiety effects on negative affect and affect-management coping for individuals diagnosed with alpha-1 antitrypsin deficiency. Health Commun. 2018;33(4):363–71.

    Article  PubMed  Google Scholar 

  34. Buchman SL, Fouche AS, Saunders EF, Craig TJ. Depression and anxiety in patients with alpha-1-antitrypsin deficiency. Ann Allergy Asthma Immunol. 2013;111(5):A42.

    Google Scholar 

  35. Sandhaus RA, Ellis P, Holm K, Choate R, Mannino D, Stockley RA, Turner AM. Augmentation therapy for alpha-1 antitrypsin deficiency: improved survival and quality of life compared to matched augmentation naive controls followed for up to 15 years. Am J Respir Crit Care Med. 2020;201(1):66.

    Google Scholar 

  36. Sandhaus RA, Strange C, Zanichelli A, Skålvoll K, Koczulla AR, Stockley RA. Improving the lives of patients with alpha-1 antitrypsin deficiency. Int J COPD. 2020;15:3313–22.

    Article  CAS  Google Scholar 

  37. Beiko T, Woodford D, Strange C. Anxiety in a population tested for alpha-1 antitrypsin deficiency. Eur Respir J. 2019;54:66.

    Google Scholar 

  38. Redondo MT, Campoa E, Saganha S, Sucena M. Health-related quality of life in patients with alpha-1 antitrypsin deficiency. Eur Respir J. 2015;46:66.

    Google Scholar 

  39. Molloy M, O’Connor C, Fee L, Carroll TP, McElvaney NG. Real life treatment benefit of intravenous augmentation therapy for severe alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2017;195:66.

    Google Scholar 

  40. Sandhaus RA, Strange C, Holm KE. Pilot study of o2asis: a novel, closed-system heated humidification device for individuals with copd requiring supplemental oxygen at home. Am J Respirat Crit Care Med. 2022;205(1):66.

    Google Scholar 

  41. Beiko T, Strange C. Anxiety and depression in patients with alpha-1 antitrypsin deficiency: current insights and impact on quality of life. Ther Clin Risk Manag. 2019;15:959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gauvain C, Mornex JF, Pison C, Cuvelier A, Balduyck M, Pujazon MC, et al. Health-related quality of life in patients with alpha-1 antitrypsin deficiency: the french experience. COPD. 2015;12(Suppl 1):46–51.

    Article  PubMed  Google Scholar 

  43. O’Connor C, Moore Z, McElvaney NG. Is there a difference in health related quality of life between family screened alpha one antitrypsin deficiency individuals and symptomatically screened individuals? Am J Respir Crit Care Med. 2011;183(1):66.

    Google Scholar 

  44. Hoth KF, Wamboldt FS, Strand M, Ford DW, Sandhaus RA, Strange C, et al. Prospective impact of illness uncertainty on outcomes in chronic lung disease. Health Psychol. 2013;32(11):1170–4.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mobeen F, Edgar RG, Pye A, Stockley RA, Turner AM. Relationship between depression and anxiety, health status and lung function in patients with alpha-1 antitrypsin deficiency. COPD J Chronic Obstr Pulmon Dis. 2021;18(6):621–9.

    Article  Google Scholar 

  46. Williams PH, Shore L, Sineath M, Quill J, Warner B, Keith J, et al. Genetics’ influence on patient experiences with a rare chronic disorder. A photovoice study of living with alpha-1 antitrypsin deficiency. Nurs Clin N Am. 2013;48(4):627–36.

    Article  Google Scholar 

  47. Smith RA, Wienke S, Coffman DL. Alpha-1 couples: Interpersonal and intrapersonal predictors of spousal communication and stress. J Genet Couns. 2014;23(2):212–20.

    Article  PubMed  Google Scholar 

  48. US Food Drug Administration. Chronic obstructive pulmonary disease: Use of the st. George’s respiratory questionnaire as a pro assessment tool guidance for industry; 2021.

  49. Critical Path Institute. C-path launches consortium for alpha-1 antitrypsin deficiency 2024. https://c-path.org/c-path-launches-consortium-for-alpha-1-antitrypsin-deficiency/.

  50. US Food and Drug Administration. Patient-focused drug development: Methods to identify what is important to patients; guidance for industry, food and drug administration staff, and other stakeholders; 2022.

  51. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56(6):893–7.

    Article  CAS  PubMed  Google Scholar 

  52. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the berlin questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131(7):485–91.

    Article  CAS  PubMed  Google Scholar 

  53. Gilbert L, Puri A, Novakovic S, Shuster J, Brantly M, Berry R, et al. Evaluation of sleep disorders in patients with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2011;183(1):66.

    Google Scholar 

  54. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377–81.

    Article  CAS  PubMed  Google Scholar 

  55. Chung J, Ataya A, Nolte J, Segui VA, Brantly ML, Benninger L. The effect of the environment on outdoor six-minute walk test performance in individuals with alpha-1 antitrypsin deficiency and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;197(MeetingAbstracts):66.

    Google Scholar 

  56. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax. 1987;42(10):773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Williams JE, Singh SJ, Sewell L, Guyatt GH, Morgan MD. Development of a self-reported chronic respiratory questionnaire (crq-sr). Thorax. 2001;56(12):954–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. van Dijk M, Gan CT, Koster TD, Wijkstra PJ, Slebos D-J, Kerstjens HA, et al. Treatment of severe stable copd: the multidimensional approach of treatable traits. ERJ Open Res. 2020;6(3):66.

    Google Scholar 

  59. Pillai A. Utility of the new gold classification for copd in alpha one antitrypsin deficiency. University of Birmingham; 2017.

  60. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline LN. Development and first validation of the copd assessment test. Eur Respir J. 2009;34(3):648–54.

    Article  CAS  PubMed  Google Scholar 

  61. Hogarth D. Endobronchial valve treatment of severe emphysema in patients with alpha-1 antitrypsin deficiency. Chest. 2019;156(4):A1771–2.

    Article  Google Scholar 

  62. Fromme M, Arslanow A, Hamesch K, Mandorfer M, Schneider CV, Lindhauer C, et al. Metabolic alterations in adults with homozygous alpha1-antitrypsin deficiency (pi∗zz genotype). Hepatology. 2019;70(suppl1):1168.

    Google Scholar 

  63. Delage A, Hogarth DK, Zgoda M, Reed M. Endobronchial valve treatment in patients with severe emphysema due to alpha-1 antitrypsin deficiency. Eur Respir Journal. 2019;54:66.

    Google Scholar 

  64. van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. Development, validity and responsiveness of the clinical copd questionnaire. Health Qual Life Outcomes. 2003;1:13.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Eisner MD, Omachi TA, Katz PP, Yelin EH, Iribarren C, Blanc PD. Measurement of copd severity using a survey-based score: validation in a clinically and physiologically characterized cohort. Chest. 2010;137(4):846–51.

    Article  PubMed  Google Scholar 

  66. Eisner MD, Trupin L, Katz PP, Yelin EH, Earnest G, Balmes J, Blanc PD. Development and validation of a survey-based copd severity score. Chest. 2005;127(6):1890–7.

    Article  PubMed  Google Scholar 

  67. Miravitlles M, Llor C, Castellar R, Izquierdo I, Baró E, Donado E. Validation of the copd severity score for use in primary care: the nerea study. Eur Respir J. 2009;33(3):519.

    Article  CAS  PubMed  Google Scholar 

  68. Foil KE, Blanton MG, Sanders C, Kim J, Al Ashry HS, Kumbhare S, Strange C. Sequencing alpha-1 mz individuals shows frequent biallelic mutations. Pulm Med. 2018;2018:2836389.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Brown KL, Sanders C, Kim J, Al Ashry HS, Blanton G, Beiko T, Strange CB. Next generation sequencing of alpha-1 antitrypsin deficiency mz individuals shows frequent bi-allelic mutations. Am J Respir Crit Care Med. 2017;195:66.

    Google Scholar 

  70. Johns MW. A new method for measuring daytime sleepiness: the epworth sleepiness scale. Sleep. 1991;14(6):540–5.

    Article  CAS  PubMed  Google Scholar 

  71. Sommerwerck U, Rabis T, Kleibrink BE, Langguth N, Wang Y, Moraides I, et al. Sleep quality and sleep-disordered breathing in lung transplant recipients. Eur Respir J. 2012;40:66.

    Google Scholar 

  72. Devlin N, Roudijk B, Ludwig K. Value sets for eq-5d-5l: a compendium, comparative review and user guide. Berlin: Springer; 2022.

    Book  Google Scholar 

  73. Ejiofor SI, Stockley RA. Health status measurements in alpha-1antitrypsin deficiency (aatd). Eur Respir J. 2015;46:66.

    Google Scholar 

  74. Karl FM, Holle R, Bals R, Greulich T, Jörres RA, Karch A, et al. Costs and health-related quality of life in alpha-1-antitrypsin deficient copd patients. Respir Res. 2017;18(1):66.

    Article  Google Scholar 

  75. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  76. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–70.

    Article  CAS  PubMed  Google Scholar 

  78. Holm K, Sandhaus R, Ford DW, McClure R, Strange C. Differences in adjustment between individuals with alpha-1 antitrypsin deficiency (aatd) associated copd and non-aatd copd. Am J Respir Crit Care Med. 2010;181(1):66.

    Google Scholar 

  79. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester cough questionnaire (lcq). Thorax. 2003;58(4):339–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vyas A, Quittner AL, Vyas D, Waterer GW, Metersky ML. Quality of life in patients with bronchiectasis treated at a dedicated bronchiectasis center. Am J Respir Crit Care Med. 2012;185:66.

    Google Scholar 

  81. McKenna SP, Meads DM, Doward LC, Twiss J, Pokrzywinski R, Revicki D, et al. Development and validation of the living with chronic obstructive pulmonary disease questionnaire. Qual Life Res. 2011;20(7):1043–52.

    Article  PubMed  Google Scholar 

  82. Portenoy RK, Thaler HT, Kornblith AB, Lepore JM, Friedlander-Klar H, Kiyasu E, et al. The memorial symptom assessment scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer. 1994;30a(9):1326–36.

    Article  CAS  PubMed  Google Scholar 

  83. Jablonski A, Gift A, Cook KE. Symptom assessment of patients with chronic obstructive pulmonary disease. West J Nurs Res. 2007;29(7):845–63.

    Article  PubMed  Google Scholar 

  84. Ford DW, Holm K, Strange C. Health related quality of life and symptom burden among patients with alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med. 2010;181(1):66.

    Google Scholar 

  85. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the medical research council (mrc) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mishel MH. The measurement of uncertainty in illness. Nurs Res. 1981;30(5):258–63.

    Article  CAS  PubMed  Google Scholar 

  87. Hoth KF, Ford D, Sandhaus RA, Strange C, Wamboldt F, Holm K. Prospective association between alcohol use and er visits in individuals with alpha-1 antitrypsin deficiency (attd) associated copd. Am J Respir Crit Care Med. 2011;183(1):66.

    Google Scholar 

  88. Hoth KF, Wamboldt FS, Ford DW, Sandhaus RA, Strange C, Bekelman DB, Holm KE. The social environment and illness uncertainty in chronic obstructive pulmonary disease. Int J Behav Med. 2015;22(2):223–32.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213.

    Article  CAS  PubMed  Google Scholar 

  90. Quittner AL, Marciel KK, Salathe MA, O’Donnell AE, Gotfried MH, Ilowite JS, et al. A preliminary quality of life questionnaire-bronchiectasis: a patient-reported outcome measure for bronchiectasis. Chest. 2014;146(2):437–48.

    Article  PubMed  Google Scholar 

  91. Quittner AL, O’Donnell AE, Salathe MA, Lewis SA, Li X, Montgomery AB, et al. Quality of life questionnaire-bronchiectasis: Final psychometric analyses and determination of minimal important difference scores. Thorax. 2015;70(1):12–20.

    Article  PubMed  Google Scholar 

  92. Ware J, Kosinski M, Bjorner J, Turner-Bowker D, Gandek B, Maruish M. User's manual for the sf-36v2® health survey. Lincoln: QualityMetric Incorporated; 2007.

  93. Durkan E, Carroll T, Moyna NM, McElvaney NG. Exercise capacity may be more strongly associated with health status in alpha-1 antitrypsin copd patients than in alpha-1 antitrypsin replete copd patients. Am J Respir Crit Care Med. 2019;199(9):66.

    Google Scholar 

  94. Ponce MC, Sandhaus RA, Campos MA. The relation of body mass index and health related quality of life in subjects with alpha 1-antitrypsin deficiency and copd. Am J Respir Crit Care Med. 2014;189:66.

    Google Scholar 

  95. Lascano J, Salathe M, Alazemi S, Zhang G, Wanner A, Sandhaus R, Campos M. Relation between body mass index and health-related quality of life in subjects with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2010;181(1):66.

    Google Scholar 

  96. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The st. George’s respiratory questionnaire. Am Rev Respir Dis. 1992;145(6):1321–7.

    Article  CAS  PubMed  Google Scholar 

  97. Everaerts S, Hartman JE, Van Dijk M, Koster TD, Slebos DJ, Klooster K. Bronchoscopic lung volume reduction in patients with emphysema due to alpha-1 antitrypsin deficiency. Respiration. 2022;6:66.

    Google Scholar 

  98. Stockley JA, Stockley RA, Sapey E. Cross-sectional assessment of small airways tests in identifying early disease in alpha-1 antitrypsin deficiency. Thorax. 2018;73:A225.

    Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

RM and KS received funding from Eli Lilly and Company to conduct the study.

Author information

Authors and Affiliations

  1. Eli Lilly and Company, Indianapolis, USA

    Ekin Seçinti, Laure Delbecque, John Krege & Sarah E. Curtis

  2. Vector Psychometric Group, LLC, Chicago, USA

    Karolina Schantz

  3. Vector Psychometric Group, LLC, Chapel Hill, NC, USA

    Rikki Mangrum

Authors
  1. Ekin Seçinti
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Karolina Schantz
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Laure Delbecque
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. John Krege
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Rikki Mangrum
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Sarah E. Curtis
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

RM and KS developed the study protocol, executed the study, conducted the analysis, and drafted the manuscript. LD, ES, SC, and JK conceptualized the study, provided analytic support for the development of domains and concepts, and contributed intellectually to the writing of the manuscript.

Corresponding author

Correspondence to Karolina Schantz.

Ethics declarations

Ethical approval and consent to participate

Not applicable to this review study.

Consent for publication

Not applicable (no individual data included).

Competing interests

RM and KS report no competing interests. LD, ES, SC and JK are employees and shareholders of Eli Lilly and Company.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seçinti, E., Schantz, K., Delbecque, L. et al. Patient-centered assessment of treatment for alpha-1 antitrypsin deficiency: literature review to identify concepts and measures for people with alpha1-antitrypsin deficiency. Orphanet J Rare Dis 20, 83 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13023-025-03592-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13023-025-03592-9

Keywords

Orphanet Journal of Rare Diseases

ISSN: 1750-1172